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  • 1. Stickler Syndrome: A Physician’s Overview
  • 2. What do you hear?
    • It could just be
    • a Zebra and
    • not a Horse!
  • 3. Stickler Syndrome: The Basics
    • Progressive, genetic connective tissue disorder
    • Autosomal dominant
    • High degree of penetrance
    • Wide range of severity/ expression
    • Affects both sexes/ all ethnicities
    • Believed to be the most common connective tissue disorder
  • 4. Stickler Syndrome: History
    • First defined by Dr. Gunnar B. Stickler, a pediatrician at Mayo Clinic, in 1965
    • Based on evaluation of 12 year old boy with vision, joint problems; had blind mother; other family members had been seen by Dr. Charles Mayo dating back to 1887
    • Multi-disciplinary team studied five generations of boy’s family
    • Originally published under name Hereditary Progressive Arthro-Ophthalmopathy
  • 5. Stats and Specs
    • Mutations found in three collagen genes to date
    • Prevalence between 1 in 7500 and 1 in 3300
    • Frequently misdiagnosed or undiagnosed
      • Average age of children diagnosed - 4.2 years
      • Average age of adults diagnosed - 32 years
      • One study found 53% error rate in original diagnosis of patients later determined to have Stickler syndrome
      • 10% of children born with cleft palate and 12% of children diagnosed at birth with Pierre-Robin sequence were later found to have Stickler syndrome
    • Problems with vision, hearing, bones/ joints and oro-facial features
  • 6. Stickler Faces
  • 7. Clinical Findings – Ocular
    • Myopia (mild to severe)
      • Present at birth
      • Minimal progression
    • Retinal Detachment/Degeneration
      • Spontaneous
      • Giant tears/ holes
      • Bilateral
      • Patient typically under age 30
    • Cataracts
      • Pre-senile
      • Wedge or comma shaped
      • Vitreous anomalies/degeneration
      • Glaucoma
      • Astigmatism/ Strabismus
  • 8. Clinical Findings - Auditory
    • Sensorineural hearing loss
    • Conductive hearing loss
    • Otitis media
    • Hypermobile tympanic membranes
    • Ears tend to be low set
  • 9. Clinical Findings – Musculo-skeletal
    • Early onset osteoarthritis
      • Usually most severe in hips and knees
    • Abnormality to ends of long bones
    • Spinal abnormalities
      • Scoliosis
      • Kyphosis (Scheuermann-like)
      • Schmorl’s nodes
      • Platyspondylia
      • Endplate abnormalities
      • Spondylolisthesis
    • Femoral head flattening/ failure
    • Double jointedness to point of dislocation
    • Genu valgum (knock-kneed)
    • Pronated feet
  • 10. Musculo-skeletal (con’t)
    • Coxa vara( hip joint deformity)
    • Hypotonia
    • Posterior slip of capital epiphysis (Leggs-Perthes like disease)
    • Flattening of epiphyses
    • Protrusio acetabuli
    • Slender extremities, long fingers, normal height
    • Intra-articular loose bodies
    • Joint pain/ stiffness
    • Arachnodactyly
    • and more
  • 11. Jay’s Knock Knees
  • 12. Jay – pre/post knee surgery
  • 13. Graham – pre-hip surgery
  • 14. Graham – post-hip surgery
  • 15. Clinical Findings - Oro-facial
    • Flat malar/ mid-face area
    • Small lower jaw/ micrognathia
    • Posterior-placed tongue
    • Obstructive airway complications
    • Cleft palate, submucous cleft or high arched palate
    • Bifid uvula
    • Flat nasal bridge
    • Small, “button” nose
  • 16. Oro-facial (con’t)
    • Epicanthic fold or anteverted nares
    • Dental
      • Enamel hypoplasia
      • Orthodontia issues/ malocclusion
    • Symptoms become less distinctive with age
  • 17. Small Noses!
  • 18.  
  • 19. Clinical Findings - Other
    • Mitral Valve Prolapse – in question, now finding prevalence may be no higher than general population
    • Pregnancy Issues
    • And more
  • 20. Overview
  • 21. Genetic Info
    • Natural mutations, not environmental mutation
    • 10% of cases are 1 st generation, spontaneous mutations
    • 3 specific mutation locations found in collagen; other mutations not yet specified
    • Mutations are usually a premature stop codon in the region of the gene encoding the triple helical domain of the collagen molecule
    • Type 1- mutation in COL2A1- 75% of Stickler syndrome pts have this mutation; results in problems with vision, hearing, oro-facial and musculo-skeletal systems
  • 22. Genetic Info (con’t)
    • Type 2- mutation in COL11A1-same system involvement as Type 1, but Type 1 and Type 2 have visibly different vitreous architecture abnormalities-useful in determining diagnosis
    • Type 3- mutation in COL11A2- problems with auditory, oro-facial and musculo-skeletal, but not eyes (also called OSMED - oto-spondylo-megaepiphyseal dysplasia)
    • Type 4- unknown gene mutation - possibly COL5A2 or others
  • 23. Getting More Personal
    • Our Family Tree
  • 24. Family Symptoms
    • Affected Female- Age 76
      • No visual problems
      • No skeletal problems
      • Clinical findings
        • High, arched palate
      • Treatments/surgeries – none
  • 25. Family Symptoms (con’t)
    • Affected Female – Age 50
      • Vision
        • Moderate myopia
        • Retinal detachment – age 16
      • Musculo-skeletal
        • Joint pain/stiffness
        • Osteoarthritis – from teen years to current
      • Oro-facial
        • High, arched palate
        • Enamel hypoplasia
      • Treatments/surgeries
        • Scleral buckle and prophylactic laser on retinas
        • Cataract surgeries
        • Bilateral hip replacements
        • Med management
  • 26. Family Symptoms (con’t)
    • Affected Male – Age 21
      • Vision
        • High myopia
        • Retinal detachment – age 14 and age18
      • Musculo-skeletal
        • Genu valgum (Knock-kneed)
      • Oro-facial
        • High arched palate
      • Auditory
        • Severe otitis media
      • Treatments/surgeries
        • Scleral buckle and prophylactic laser on retinas
        • Scleral buckle on lasered retina
        • Knee growth plate stapling
        • Ear tubes
  • 27. Family Symptoms (con’t)
    • Affected Male – Age 15
      • Vision
        • Mild myopia
      • Musculo-skeletal
        • Femoral head failure/ necrosis
        • Femoral head too large for hip socket
        • Pronated feet
      • Oro-facial
        • Mildly arched palate
      • Treatments/surgeries
        • Prophylactic laser on retinas
        • Femur wedge osteotomy
        • Triple innonimate hip osteotomies
        • Ankle growth plate screws
        • Ankle growth plate removal
  • 28. Diagnostic Criteria
    • Based on findings of long-term NIH study
    • Evaluates molecular data, family history, characteristic ocular, auditory and skeletal abnormalities
    • 12 points possible on 9 criteria
    • Diagnosis (for Type 1 SS) requires 5 points minimum AND presence of cleft palate, ocular abnormalities or high frequency sensorineural hearing loss
  • 29. Stickler Syndrome Diagnostic Criteria
  • 30. Other Diagnostic Comments
    • Most common cause of retinal detachment in children
    • Ocular issues most often addressed retroactively, then patient later diagnosed with Stickler syndrome as other problems develop
    • Often confused with
      • Wagner’s syndrome
      • Marshall’s syndrome
      • Weissenbacher – Zweymueller’s syndrome
    • Are there undiagnosed family members?
  • 31. Management of Physical Issues
    • Ocular
      • Ophthalmologic assessment- as often as every 3-6 months in young children (children will often not complain about sight issues until the 2 nd eye is affected)
      • Normal newborns are hyperopic (+1 diopters or more), so any degree of myopia is suspect
      • Prophylactic laser photocoagulation or kryo treatment on retinas (UK is also doing prophylactic scleral buckling)
      • “ Evaluation under anesthesia” especially for infants and young children already diagnosed
      • Meds for glaucoma
      • Getting infants and children who have vision problems treatment (such as corrective lenses) is important for brain development
  • 32. Management Of Physical Issues
    • Auditory
      • Hearing assessment
      • Check for frequent ear infections/use antibiotic meds
      • Otolaryngology evaluation- to assess ear and/or palate abnormalities, including submucous cleft and bifid uvula
      • Evaluate need for hearing aids and speech therapy
  • 33. Management of Physical Issues
    • Oro-facial abnormalities
      • Maxillo-facial and feeding assessment, if mid-line clefting
      • Check for feeding problems
      • Speech/ swallow evaluations for all individuals with cleft abnormalities
      • Sleep study for children with breathing issues
      • Orthodontics
  • 34. Management of Physical Issues
    • Musculo-skeletal
      • Skeletal evaluation
      • Radiographic skeletal survey in childhood
      • Rheumatology consultation
      • Splints, braces, aids
      • Pain management – oral meds, incl. anti-inflammatories, joint lubricants/injections
      • Rehabilitation, physical, hydro-therapies
      • Arthroscopy/surgery
      • Appropriate exercise program to strengthen muscles around lax joints (no contact sports, diving, roller coasters)
      • Pain Clinic evaluation
  • 35. Management of Physical Issues
    • Cardiac
      • Echocardiogram (if reason to suspect mitral valve prolapse)
      • Prophylactic antibiotics (if MVP or joint replacements)
    • Genetics
      • Prenatal testing- if Stickler syndrome in family, consider CVS, amniocentesis or ultrasound; especially important to determine if cleft issues to be dealt with at time of birth
  • 36. Management of Psycho-Social Issues
    • Normal intelligence, but can be challenged by vision/ hearing/joint issues at school, work, socially
    • Normal lifespan, but impacts major life decisions such as college, career, marriage, child-bearing
    • Children and young adults deal with denial issues; want to appear normal
      • May ignore health issues
      • Problems may be minimized by parents or teachers
  • 37. Management of Psycho-Social Issues (con’t)
    • School issues
      • Manage absences due to doctor appts/surgeries and hospitalizations
      • Awareness of bullying and teasing
      • Potentially eliminate PE class or modify involvement
    • Work with parent on acceptance and communication
    • Encourage parent to educate themselves on IEP (Individual Education Plan) and 504 plans
    • Counseling for patients and family members
    • Address sibling issues
  • 38. Resources/Support - U.S.
    • Stickler Involved People
      • 501(c)(3), not-for-profit, all volunteer organization
      • Mission - educate and give support to all those affected by Stickler syndrome
      • Contact Information
        • www.sticklers.org
        • [email_address]
      • Support Services
        • Annual Conference
        • List serve
        • Quarterly newsletter
        • Educational and support services
        • DVD (copy can be ordered at www.sticklervideo.org )
        • Brochures
  • 39. More Resources
    • Dave Hawley’s Stickler Syndrome Page
        • http://members.aol.com/dhawley/stickler.html
    • National Organization for Rare Diseases
      • www.rarediseases.org
      • Free Physician’s Guides available (for 9 rare diseases so far)
      • On-line summaries for over 1100 rare diseases
    • National Coalition for Health Professional Education in Genetics (NCHPEG)
      • www.nchpeg.org
    • National Institute of Child Health and Human Development
      • www.nichd.nih.gov
  • 40. SIP goal: to educate physicians
    • Increase awareness, especially of primary care physicians
    • Why?
      • NIH and Stickler Group Survey Results
      • 1997-NIH initiated a long-term study of Stickler syndrome patients
      • 1998 and 2001 Stickler support groups in US, UK, the Netherlands and Canada surveyed their members
    • Results (of 330 returned surveys)
      • Age at Diagnosis
        • Infants – 9%
        • Childhood/ Young Adults - 73%
        • Adults over age 30 – 18%
      • Diagnosed By –
        • Genetics- 42%
        • Ophthalmologists- 38%
        • Pediatricians- 8%
        • Other Specialties- 12%
  • 41. Survey Results
    • Diagnosed individuals –childhood symptoms
        • 90%- myopia
        • 41%- frequent ear infections
        • 24%- knock-kneed
        • 41%- joint pain by age 9
    • So, although not all near-sighted, knock-kneed children with ear infections and/or joint pain will have Stickler syndrome…
    • A Tipping Point to remember is:
    • You would rarely see a child with Stickler syndrome who wasn’t near sighted, knock-kneed, having joint pain and/ or ear infections
  • 42. What do you do?
    • If you see some combination of myopia, characteristic facial features, hearing loss, skeletal abnormalities, and cleft issues in a 1 year old, you might suspect Stickler syndrome. Then,
      • Refer to a geneticist
      • Give the family internet site information for them to review
        • Likely to help with acceptance, if that is an issue
        • Allows them to come to the conclusion to seek geneticist’s opinion and/or treatment
      • Multi-disciplinary, TEAM approach with specialists, therapists, educators
  • 43. Not So Different
    • Sometimes that zebra and that horse look almost the same!
    • You may well see a Stickler syndrome zebra. Will you recognize it?
  • 44. References
    • Hughes, Wendy - Stickler Syndrome Support Group (UK). Stickler Syndrome - A Child in Your Care . 11/2000.
    • Hughes, Wendy - Stickler Syndrome Support Group (UK). Stickler Syndrome - A Diagnostic Aid for Professionals . 11/2004.
    • Francomano, Clair, Wilkin, Douglas J., Liberfarb, Ruth M. "Stickler Syndrome." Management of Genetic Syndromes . : Wiley Liss, Inc. , 2005.
    • Rose, Peter S., Levy, Howard P., Liberfarb, Ruth M., Davis, Joie, Szymko-Bennett, Y., Rubin, Benjamin I., Tsilou, Ekaterini, Griffith, Andrew J., Francomano, Clair A., "Stickler Syndrome: Clinical Characteristics and Diagnostic Criteria." American Journal of Medical Genetics . 138A (2005). 199-207.
    • Robin, MD, Nathaniel H., Warmen, MD, Matthew L.. "Stickler Syndrome." geneclinics.org . June 8, 2000. Gene Clinics. 13 July 2001. http://www.geneclinics.org/profiles/stickler/details.
    • Rose, BS, MD, Peter S., Levy, MD, PhD, Howard P., et al., "Thoracolumbar Spinal Abnormalities in Stickler Syndrome." Spine . 26 (2001). 403-409.